Assessing the sensitivity of [¹¹C]p943, a novel 5‐HT_IB radioligand, to endogenous serotonin release

Abstract

The main objective of the current study was to determine the sensitivity of the PET radioligand [11C]P943 to fenfluramine-induced changes in endogenous 5-HT in nonhuman primate brain. Fenfluramine-induced changes in 5-HT1B occupancy were compared to those obtained by self-block with unlabeled P943. Two baboons and 1 rhesus monkey were given preblocking or displacing doses of fenfluramine (1–5 mg/kg) or preblocking doses of unlabeled P943 (0.2 mg/kg) and imaged with [11C]P943 PET. Receptor occupancy by the low dose of fenfluramine (1 mg/kg) in the baboons was 25% and 29% and by the high dose of fenfluramine (5 mg/kg) in the rhesus macaque was 42%. Receptor occupancy by P943 (0.2 mg/kg) was 68% and 86% in the baboons. PET imaging of 5-HT1B receptors with [11C]P943 may be a useful approach for measuring changes in endogenous 5-HT in the living human brain.

Serotonin transporter occupancy by escitalopram and citalopram in the non-human primate brain: a [11C]MADAM PET study

“…We previously demonstrated that the potent serotonin releaser fenfluramine reduced the binding of the 5-HT 1B receptor radioligand [ 11 C]AZ10419369 in non-human primates by up to 50 % (Finnema et al 2010(Finnema et al , 2012, and similar results have been reported by others using the 5-HT 1B receptor radioligand [ 11 C]P943 (Cosgrove et al 2011;Ridler et al 2011) or the 5-HT 1A receptor radioligand [ 11 C]CUMI-101 (Milak et al 2011). The effects of single SSRI doses have also been evaluated in anaesthetized non-human primates (NHPs) in preparation for studies in human.…”

Reductions in Brain 5-HT1B Receptor Availability in Primarily Cocaine-Dependent Humans

“…Any possible preexisting differences in CD could be supported by a host of genetic studies in addiction (13, 31) and inherent 5-HT 1B heterogeneity could potentially alter dopamine activity in reward areas by reducing inhibition of GABA release. (30) Potential extracellular 5-HT affects on 5-HT 1B are also an important consideration and given that 5-HT levels were increased in a human post-mortem CD sample (32) and [ 11 C]P943 has been shown to be sensitive to endogenous 5-HT in the nonhuman primate (33), elucidation of this possible affect should be made to further interpretations of 5-HT 1B in CD.…”

OCD is associated with an altered association between sensorimotor gating and cortical and subcortical 5-HT1b receptor binding

“…11 C-P943 binding has been shown to be sensitive to changes in 5-HT levels, as well as variation in receptor density (71). One explanation for our results, therefore, is that they reflect a change in the relationship between basal 5-HT and PPI in OCD.…”

“…5-HT 1B receptor availability can be assessed in vivo in humans using the PET ligands 11 C-P943 (71-74) and 11 C-AZ10419369 (75). 11 C-P943 has recently been used to document receptor abnormalities in several psychiatric conditions (76-78).…”